• Known hypersensitivity to carbamazepine (4)
`• Known hypersensitivity to tricyclic antidepressants (4)
`• Concomitant use with monoamine oxidase inhibitors (MAOIs) or use within
`14 days of discontinuing an MAOI (4)
`
`• Concomitant use with delavirdine or other non-nucleoside reverse
`transcriptase inhibitors. EQUETRO decreases efficacy of these drugs (4, 5.9)
`• Concomitant use of nefazodone (4)
`
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`• Drug Reaction with Eosinophilia and Systemic Symptoms: Monitor for
`hypersensitivity. Discontinue if another cause can not be established (5.3)
`• Suicidal Behavior and Ideation: Monitor for depression, suicidal thoughts or
`
`behavior, and/or any unusual changes in mood or behavior (5.4)
`
`
`• Embryofetal Toxicity: Advise women of child-bearing potential of possible
`risks to the fetus (5.4, 8.1)
`
`
`• Abrupt Discontinuation and Risk of Seizure: Taper the dose when
`
`discontinuing treatment (5.6).
`
`
`• Hyponatremia: Consider discontinuing EQUETRO in patients with
`significant symptomatic hyponatremia (5.7).
`
`
`• Cognitive and Motor Impairment: Advise patients not to drive or operate
`
`machinery until they have gained sufficient experience on EQUETRO to
`gauge whether it adversely affects these activities (5.8)
`
`
`• Hepatic Porphyria: Avoid EQUETRO use in patients with hepatic porphyria:
`
`
`can cause acute episodes of porphyria (5.10)
`
`------------------------------ADVERSE REACTIONS------------------------------
`---------------------------RECENT MAJOR CHANGES----------------------------
`Most common (>5% and 2 times placebo) adverse reactions were dizziness,
`
`Contraindications, concomitant use with delavirdine or other non-nucleoside
`somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth,
`
`
`
`reverse transcriptase inhibitors (4, 5.9) ----------------------------- 11/2012
`
`
`asthenia, rash, blurred vision, and speech disorder (6.1)
`
`Contraindications, concomitant use with nefazodone (4) ------------ 11/2012
`
`
`Warnings and Precautions, drug reaction with eosinophilia and systemic
`To report SUSPECTED ADVERSE REACTIONS, contact Validus
`
`
` symptoms (5.3) and hepatic porphyria (5.10) ----------------------- 11/2012
`
`
`
`Pharmaceuticals LLC at 1-866-9VALIDUS or FDA at 1-800-FDA-1088 or
`----------------------------INDICATIONS AND USAGE----------------------------
`www.fda.gov/medwatch
`
`EQUETRO is a mood stabilizer indicated for the treatment of acute manic or
`
`
`mixed episodes associated with bipolar I disorder (1)
`
`---------------------------------DRUG INTERACTIONS----------------------------
`Cytochrome (CYP) 3A4 inhibitors, epoxide hydrolase inhibitors, CYP3A4
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`inducers, drugs metabolized by CYP1A2 or CYP3A4 (oral contraceptives,
`• Recommended initial dose of EQUETRO: 200 mg twice daily (2.1)
`
`
`
`delavirdine, nefazodone), phenytoin, CNS depressants, lithium, chloroquine,
`
`• Adjust dose in 200-mg increments to achieve optimal clinical response (2.1)
`
`mefloquine (7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8)
`
`• When discontinuing treatment, reduce dose gradually (2.1, 5.7)
`
`• Monitoring serum carbamazepine concentrations may be useful in dose
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`selection and miniziming risk of toxicity (2.2)
`
`
`
`Pregnancy: Can cause fetal harm. (5.5, 8.1)
`
`
`
`• Take capsules whole or open capsules and sprinkle beads over food (2.4)
`
`
`Nursing Mothers: Discontinue drug or discontinue nursing, taking into
`
`consideration importance of drug to mother (8.3)
`
`
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`
` Extended-Release Capsules: 100 mg, 200 mg, and 300 mg (3)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`------------------------------CONTRAINDICATIONS-------------------------------
`
`
`• Bone marrow depression (4)
`
`
`
`Serious Dermatologic Reactions
`
`
`• Serious and sometimes fatal dermatologic reactions, including toxic
`epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS),
`
`have occurred with EQUETRO (5.1)
`
`• Patients of Asian ancestry have a 10-fold greater risk of TEN/SJS,
`compared to other populations. In genetically at-risk patients, test for
`
`
`the HLA-B*1502 allele prior to initiating EQUETRO (2.3, 5.1)
`
`
`• Discontinue EQUETRO if these reactions occur (5.1)
`
`Aplastic Anemia and Agranulocytosis
`
`• Aplastic anemia and agranulocytosis occurred with EQUETRO (5.2)
`• Obtain complete pretreatment hematological testing. Consider
`discontinuing EQUETRO if significant bone marrow depression
`develops (2.3, 5.2)
`
`
`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`EQUETRO safely and effectively. See full prescribing information for
`
`EQUETRO.
`
`EQUETRO (carbamazepine) extended-release capsules, for oral use
`
`Initial U.S. Approval: 1968
`
`
`WARNING: SERIOUS DERMATOLOGIC REACTIONS
`
`and APLASTIC ANEMIA AND AGRANULOCYTOSIS
`
`See full prescribing information for complete boxed warning.
`
`
`
` Revised: November 2012
`
`
`1
`
`
`
`Reference ID: 3216024
`
`Page 1 of 19
`
`JAZZ EXHIBIT 2011
`Amneal Pharms. LLC (Petitioner) v. Jazz Pharms. Ireland LTD. (Patent Owner)
`Case IPR2016-00546
`
`

`
` Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`
`7.1
`Pharmacokinetic Effects of Other Drugs on Equetro
`
`7.2
` Pharmacokinetic Effects of Equetro on Other Drugs
`
`7.3
`Pharmacodynamic Drug Interactions
`
`USE IN SPECIFIC POPULATIONS
` Pregnancy
`
`8.1
`
`Labor and Delivery
`
`8.2
`
`8.3
` Nursing Mothers
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`OVERDOSAGE
`
`Human Experience
`10.1
`10.2
`Management of Overdosage
`
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`CLINICAL STUDIES
`Bipolar I Disorder (Acute Manic or Mixed Episodes)
`
`14.1
`
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
` 
`How Supplied
`16.1
`16.2
`Storage
`PATIENT COUNSELING INFORMATION
`17
` 
` 
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
` 
`
`2
`
`
`
`7
`
`8
`
`10
`
`11
`12
`
`13
`
`14
`
`16
` 
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS DERMATOLOGIC REACTIONS and
`
` APLASTIC ANEMIA AND AGRANULOCYTOSIS
`1
`INDICATIONS AND USAGE
`
` 1.1 Acute Manic or Mixed Episodes associated with Bipolar I Disorder
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
` Dosing Information
`2.1
`Monitoring Serum Carbamazepine Concentration
`
`2.2
`
`Laboratory Testing Prior to Dosing
`
`2.3
`2.4
` Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Serious Dermatological Reactions
`
`5.2
`Aplastic Anemia and Agranulocytosis
`
`5.3
`Drug Reaction with Eosinophilia and Systemic
`
`
`Symptoms/Multiorgan Hypersensitivity
`
`Suicidal Behavior and Ideation
`
` Embryofetal Toxicity
`
`
`Abrupt Discontinuation and Risk of Seizure
`
` Hyponatremia
`Potential for Cognitive and Motor Impairment
`
`Decreased Antiviral Effect of Non-nucleoside Reverse
`
`Transcriptase Inhibitors with Concomitant use of
`
`EQUETRO
`
`Hepatic Porphyria
`5.10
` Increased Intraocular Pressure
`
`5.11
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`
`
`5.4
`5.5
`5.6
`5.7
`5.8
`5.9
`
`2
`
`3
`4
`5
`
`6
`
`
`
`Reference ID: 3216024
`
`Page 2 of 19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
` WARNING: SERIOUS DERMATOLOGIC ADVERSE REACTIONS and APLASTIC ANEMIA AND
`
`AGRANULOCYTOSIS
`
`
`Serious Dermatologic Reactions and HLA-B*1502 Allelle
`
`
`
`Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
`
`
`Stevens-Johnson Syndrome (SJS), have occurred in patients treated with carbamazepine. These
`syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash occur. These
`
`reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian
`
`
`populations, but the risk in patients of Asian descent is estimated to be about 10 times higher. There is a
`
`strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an
`
`
`inherited allelic variant of the HLA-B gene that is found almost exclusively in patients with Asian
`ancestry. Test for HLA-B*1502, prior to initiating EQUETRO in patients with an increased likelihood of
`
`carrying this allele. Avoid use of EQUETRO in patients testing positive for the allele unless the benefit
`clearly outweighs the risk. Discontinue EQUETRO if you suspect that the patient has a serious
`
`
`
`dermatologic reaction [see Warnings and Precautions (5.1)].
`
`
`
`
`Aplastic Anemia and Agranulocytosis
`
`
`Aplastic anemia and agranulocytosis can occur during treatment with EQUETRO. The risk of
`
`
`developing these reactions with EQUETRO is 5-8 times greater than in the general population. However,
`
`the overall risk in the general population is low (6 cases in a population of one million per year for
`
`agranulocytosis and two cases in a population of one million per year for aplastic anemia). Obtain a
`complete blood count before beginning treatment with EQUETRO, and monitor CBC periodically.
`Consider discontinuing if EQUETRO if significant bone marrow depression develops [see Warnings and
`Precautions (5.2)].
`
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`1.1 Acute Manic or Mixed Episodes associated with Bipolar I Disorder
`
`
`EQUETRO is indicated for treatment of patients with acute manic or mixed episodes associated with bipolar I disorder.
`
`
`
`The efficacy of EQUETRO in acute mania was established in 2 randomized, double-blind, placebo-controlled,
`
`
`3-week studies in adult patients meeting DSM-IV criteria for bipolar I disorder who had an acute manic or mixed
`
`episode [see Clinical Studies (14.1)]. The effectiveness of EQUETRO for longer-term use and for prophylactic use
`
`in mania has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use
`
`
`
`EQUETRO for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the
`
`individual patient.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`
`
`The recommended initial dose of EQUETRO is 200 mg administered twice daily. The dose may be increased by 200
`
`
`
`
`
`mg per day to achieve optimal clinical response. Doses higher than 1600 mg per day have not been studied in mania
`associated with bipolar disorder.
`
`
`
`
`
`When discontinuing treatment, reduce the dose gradually and avoid abrupt discontinuation in order to decrease the
`risk of seizure [see Warnings and Precautions (5.6)].
`
`
`2.2 Monitoring Serum Carbamazepine Concentration
`
`
`
`Reference ID: 3216024
`
`Page 3 of 19
`
`

`
`
`
`
`
`
`
`
`
`Monitoring serum carbamazepine concentrations may be useful for dose selection, minimizing toxicity, and
`
`
`verifying drug compliance, especially in clinical conditions in which alterations in EQUETRO metabolism can
`
`occur (e.g., drug interactions) [see Drug Interactions (7)].
`
`2.3 Laboratory Testing Prior to Dosing
`
`
`
`
`Prior to initiating treatment with EQUETRO, test patients with ancestry in genetically at-risk populations for the
`
`presence of the HLA-B*1502 allele. The high resolution genotype test is positive if one or two HLA-B*1502 alleles
`are present. Avoid use of EQUETRO in patients testing positive for the allele, unless the benefit clearly outweighs
`the risk [see Boxed Warning, Warnings and Precautions (5.1)].
`
`
`Prior to initiating EQUETRO in all patients, obtain a pre-treatment complete blood count including platelets and
`differential. Monitor CBC periodically [see Warnings and Precautions (5.2)].
`
`2.4 Administration Instructions
`
`
`
`The EQUETRO capsules may be taken orally or may be opened and the beads sprinkled over food, such as a
`
`
`
`teaspoon of applesauce. Do not crush or chew EQUETRO capsules. EQUETRO can be taken with or without meals.
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`EQUETRO (carbamazepine) extended-release capsules for oral administration is supplied in three dosage strengths:
`
`
`
`•
`
`
`
`
`100 mg — Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with
`
`
`
`SPD417 on one end and SPD417 and 100 mg on the other in white ink
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`200 mg — Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417
`
`
`on one end and SPD417 and 200 mg on the other in white ink.
`
`
`
`
`300 mg — Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one
`
`end and SPD417 and 300 mg on the other in white ink.
`
`
`4 CONTRAINDICATIONS
`
`
`• Bone marrow depression [see Warnings and Precautions (5.2)].
`
`
`
`
`
`• Known hypersensitivity to carbamazepine, such as anaphylaxis or serious hypersensitivity reaction [see
`Warnings and Precautions (5.3)].
`
`
`
`
`• Known hypersensitivity to any of the tricyclic compounds (e.g., amitriptyline, desipramine, imipramine,
`protriptyline, and nortriptyline. Hypersensitivity reactions include anaphylaxis and serious rash.
`
`
`
`• Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors. EQUETRO can
`
`
`substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss
`
`of virologic response and possible resistance to these medications. [see Warnings and Precautions (5.9)
`
`
`and Drug Interactions (7.2)]
`
`
`
`
`• Concomitant use of monoamine oxidase inhibitors (MAOIs). Before beginning treatment with EQUETRO,
`
`
`
`MAOIs should be discontinued for a minimum of 14 days. Concomitant use can cause serotonin syndrome.
`
`
`
`
`• Concomitant use of nefazodone. This may result in insufficient plasma concentrations of nefazodone and
`
`its active metabolite to achieve a therapeutic effect.
`
`
`
`
`
`
`
`Reference ID: 3216024
`
`Page 4 of 19
`
`

`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`5.1 Serious Dermatologic Reactions
`
`
`
`
`Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-
`Johnson syndrome (SJS), have been reported with carbamazepine treatment. These syndromes may be accompanied
`
`
`
`
`by mucous membrane ulcers, fever, or painful rash occur. Over 90% of carbamazepine-treated patients who
`
`experienced SJS/TEN developed these reactions within the first few months of treatment. The risk of these reactions
`
`
`
`
`
`is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
`
`risk in some Asian countries is estimated to be about 10 times higher. Discontinue EQUETRO if you suspect that
`
`
`
`
`the patient has a serious dermatologic reaction. If signs or symptoms suggest SJS/TEN, do not resume treatment
`with EQUETRO.
`
`
`SJS, TEN, and HLA-B*1502 Allele
`Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
`
`
`between the risk of developing SJS/TEN with carbamazepine treatment and the presence of the HLA-B*1502 allele
`
`(an inherited variant of the HLA-B gene). Prior to initiating EQUETRO therapy in patients at higher likelihood for
`
`this allele, perform testing for HLA-B*1502. The high resolution genotype test is positive if one or two HLA­
`
`B*1502 alleles are present. Avoid use of EQUETRO in patients positive for the HLA-B*1502 allele unless the
`
`
`benefits clearly outweighs the risks of serious dermatologic reactions. Tested patients who are found to be negative
`
`
`for the allele are thought to have a low risk of SJS/TEN associated with carbamazepine treatment.
`
`
`
`The prevalence of the HLA-B*1502 allele may be higher in Asian populations: Hong Kong, Thailand, Malaysia, and
`
`
`parts of the Philippines (> 15%); Taiwan (10%), North China (4%); south Asians, including Indians (2 to 4%); and
`
`
`Japan and Korea (< 1%). HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-
`Americans, Hispanics, and Native Americans). The accuracy of estimated rates of the HLA-B*1502 allele in these
`populations may be limited by wide variability in rates within ethnic groups, the difficulty in ascertaining ethnic
`ancestry, and the likelihood of mixed ancestry.
`
`
`
`
`
`
`
`
`The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
`
`carbamazepine, such as maculopapular rash, or to predict Drug Reaction with Eosinophilia and Systemic Symptoms
`
`
`hypersensitivity syndrome or non-serious rash (maculopapular eruption [MPE]) or to predict Drug Reaction with
`
`Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.3)].
`
`
`
`Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of
`
`
`Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN, including phenytoin. Consideration
`
`
`
`
`should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when
`alternative therapies are otherwise equally acceptable.
`
`Hypersensitivity Reactions and HLA-A*3101 Allele
`
`
`Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate
`association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101, an inherited
`allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include
`
`SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings
`
`
`and Precautions (5.3)].
`
`
`
`
`
`HLA-A*3101 is expected to be present in the following frequencies: greater than 15% in patients of Japanese and
`
`
`Native American ancestry; up to about 10% in patients of Han Chinese, Korean, European, and Latin American
`
`
`
`
`
`ancestry; and up to about 5% in African-Americans and patients of Indian, Thai, Taiwanese, and Chinese (Hong
`Kong) ancestry.
`
`
`
`The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients
`
`known to be positive for HLA-A*3101.
`
`
`
`Hypersensitivity and Limitations of HLA Genotyping
`
`Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for
`
`
`appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian and HLA-A*3101
`
`
`
`Reference ID: 3216024
`
`Page 5 of 19
`
`

`
`
`
`
`
`
`
`positive patients treated with carbamazepine will not develop SJS/TEN or other hypersensitivity reactions, and these
`
`
`reactions can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity.
`The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity
`
`
`reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic
`
`monitoring have not been studied.
`
`
`5.2 Aplastic Anemia and Agranulocytosis
`
`
`Aplastic anemia and agranulocytosis have occurred in patients treated with carbamazepine. Data from a population-
`
`based case-control study suggest that the risk of developing these reactions is 5-8 times greater than in the general
`
`
`population. However, the overall risk of these reactions in the untreated general population is low, approximately six
`
`
`
`patients per one million population per year for agranulocytosis and two patients per one million population per year
`for aplastic anemia.
`
`
`Although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon in association with
`
`the use of carbamazepine, data are not available to estimate accurately their incidence or outcome. However, the vast majority
`
`
`of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis.
`Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematologic
`
`changes observed in monitoring of patients on carbamazepine are unlikely to signal the occurrence of either
`
`abnormality. Nonetheless, complete pretreatment hematological testing should be obtained as a baseline. If a patient
`
`in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be
`
`
`monitored closely. Consider discontinuing EQUETRO if any evidence of significant bone marrow depression
`
`develops. Clinical features can include fever, dyspnea on exertion, fatigue, easy bruising, petechiae, epistaxis,
`gingival bleeding, and heavy menses.
`
`5.3 Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity
`
`
`
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity,
`have occurred with carbamazepine. Some of these events have been fatal or life-threatening. DRESS typically,
`
`
`
`
`
`although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system
`
`involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling
`
`an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ
`
`
`systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g.,
`
`fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the
`
`
`
`
`patient should be evaluated immediately. Equetro should be discontinued if an alternative etiology for the signs or
`
`symptoms cannot be established.
`
`Hypersensitivity
`
`Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction
`
`
`
`
`to anticonvulsants including phenytoin, primidone, and phenobarbital. A history of hypersensitivity reactions should
`
`
`
`be obtained for patients and their immediate family members. If such history is present, benefits and risks should be
`
`carefully considered, and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be
`carefully monitored.
`
`
`In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may
`experience hypersensitivity reactions with oxcarbazepine.
`
`
`5.4 Suicidal Behavior and Ideation
`
`
`Antiepileptic drugs (AEDs), including EQUETRO, increase the risk of suicidal thoughts or behavior in patients
`
`
`
`
`taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the
`
`
`emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or
`behavior.
`
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
`showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8,
`95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which
`
`
`
`Reference ID: 3216024
`
`Page 6 of 19
`
`

`
`
`
`
`
`
`
` had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among
`
`
`
`
`
`
`
` 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
` increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four
`
`
`
`
`
`
` suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to
` allow any conclusion about drug effect on suicide.
`
`
` The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug
`
`
`treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the
`
`
`
`
`
`
`
`analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be
`assessed.
`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of
`
`increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk
`
`
`applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical
`
`
`
`trials analyzed. Table 1 presents the absolute and relative risk by indication for all evaluated AEDs.
`
`
`Table 1
`
`
`
`
`
`Indication
`
`Reactions Per
`1000 Patients
`
`Reactions Per 1000
`Patients
`
`
`
`Risk Difference: Additional Drug
`Patients with Events Per 1000 Patients
`
`
`Risk of suicidal thoughts or behavior (reactions) for antiepileptic drugs by
`indication in the pooled analysis
`Placebo
`Antiepileptic Drugs
`
`Relative Risk:
`
`Incidence of Reactions in AED
`Group/ Incidence of Reactions in
`
`Placebo Group
`3.5
`1.5
`1.9
`1.8
`
`2.4
`2.9
`0.9
`1.9
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for
`
`
`psychiatric or other conditions, but the absolute differences were similar for the epilepsy and psychiatric indications.
`
`
`Anyone considering prescribing EQUETRO or any other AED must balance the risk of suicidal thought or behavior
`
`
`with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves
`
`
`
`associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal
`
`
`thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these
`
`
`symptoms in any given patient may be related to the illness being treated.
`
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
`
`
`behaviors and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of
`
`
`
`depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts
`about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
`
`
`5.5 Embryofetal Toxicity
`
`
`EQUETRO is a Category D drug [see Use in Specific Populations (8.1)].
`
`
`EQUETRO can cause fetal harm when administered to a pregnant woman. Apprise women of childbearing potential
`
`of this risk. Use in pregnancy only if the potential benefits of treatment outweigh the risks
`
`
`Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy
`
`and congenital malformations, including spina bifida. If this drug is used during pregnancy, or if the patient becomes
`
`
`
`
`
`pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
`
`
`Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
`teratogenic effects associated with the use of anticonvulsants in combination therapy.
`
`
`
`Reference ID: 3216024
`
`Page 7 of 19
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`In humans, transplacental passage of carbamazepine is rapid (30–60 minutes), and the drug is accumulated in the
`
`fetal tissues, with higher levels found in liver and kidney than in brain and lung.
`
`Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages
`
`
`
`
`
`10–25 times a human daily dosage of 1200 mg on a mg/kg basis or 1.5–4 times the human daily dosage of 1200 mg
`on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg, and 4 of 119
`
`
`
`
`
`
`
`offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2).
`
`
`Tests to detect defects using current accepted procedures should be considered a part of routine prenatal care in
`childbearing women receiving carbamazepine.
`
`
`
`
`
`To provide additional information regarding the effects of in utero exposure to Equetro, physicians are advised to
`
`
`recommend that pregnant patients taking Equetro enroll in the North American Antiepileptic Drug (NAAED)
`
`Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients
`
`
`themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/
`
`5.6 Abrupt Discontinuation and Risk of Seizure
`
`
`
`
`
`Do not discontinue EQUETRO abruptly, because of the risk of seizure and other withdrawal signs/symptoms.
`
`
`
`Patients with seizure disorder are at increased risk of developing seizure and status epilepticus with attendant
`hypoxia and threat to life.
`
`
`
`5.7 Hyponatremia
`
`
`Hyponatremia can occur as a result of treatment with EQUETRO. In many cases, the hyponatremia appears to be
`
`
`caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH
`
`
`
`
`with EQUETRO treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at
`
`
`
`
`greater risk of developing hyponatremia. Consider discontinuing EQUETRO in patients with symptomatic
`
`
`hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency,
`
`difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.
`
`Consider discontinuing EQUETRO in patients with symptomatic hyponatremia.
`
`5.8 Potential for Cognitive and Motor Impairment
`
`
`
`
`EQUETRO has the potential to cause impairment in judgment, cognition, and motor function. Caution patients
`about operating hazardous machinery, including automobiles, until they are reasonably certain the EQUETRO does
`not affect them adversely. Adverse reactions in the clinical trials in bipolar disorder included (EQUETRO, N= 251
`
`
`
`
`and Placebo, N= 248): somnolence (32% vs. 13%), ataxia (15% vs. 0.4%), dizziness (44% vs. 12%), vertigo (2% vs.
`1%), thinking abnormal (2% vs. 0.4%), tremor 3% vs. 1%), and blurred vision (6% vs. 2%) [see Adverse Reactions
`
`(6.1)].
`
`
`5.9 Decreased Antiviral Effect of Non-nucleoside Reverse Transcriptase Inhibitors with
`Concomitant use of EQUETRO
`
`
`
`
`
`Coadministration of EQUETRO with non-nucleoside reverse transcriptase inhibitors, including delavirdine, may
`
`
`lead to loss of virologic response and possible resistance. Through induction of CYP3A4, EQUETRO can markedly
`
`decrease the concentrations of these drugs. Coadministration of delavirdine and EQUETRO can decrease
`
`
`delavirdine concentrations by 90% [see Contraindications (4), Warnings and Precautions (5.9), and Drug
`
`Interactions (7.2)].
`
`
`
`5.10 Hepatic Porphyria
`
`
`
`
`The use of EQUETRO should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
`porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving
`
`carbamazepine therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors
`
`in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
`
`
`
`
`Reference ID: 3216024
`
`Page 8 of 19
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` 5.11 Increased Intraocular Pressure
`
`
` Carbamazepine has mild anticholinergic activity. In patients with a history of increased intraocular pressure,
`
`consider assessing intraocular pressure before initiating treatment and periodically during therapy.
`
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in more detail in other sections of the labeling:
`
`
`
`
`
`
`
`• Serious dermatologic reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome [see
`
`
`Warnings and Precautions (5.1)
`
`
`
`
`• Aplastic anemia/agranulocytosis [see Warnings and Precautions (5.2)]
`
`
`
`• Drug reaction with eosinophilia and systemic symptoms/multiorgan hypersensitivity [see Warnings and
`
`